Skin cancer is the most common malignancy encountered in the US. While most occurrences of non-melanoma skin cancer can be successfully treated, the growing number of cases and the increased virulence of the malignancy in certain populations make it a significant societal risk. An example of a population at increased risk based on incidence and virulence is organ transplant recipients (OTR), a growing subset of our population due to increased graft survival and numbers of graft recipients. In most series, the incidence of skin cancers in OTR has been > 50% by 20 years post-graft. Initiators and promoters of skin epithelial tumor formation have long been observed to cause increased levels of polyamines and their rate-limiting biosynthetic enzyme ornithine decarboxylase (ODC). Conversely, compounds that decrease ODC activity inhibit skin tumor formation. Difluoromethylornithine (DFMO) is a specific inhibitor of ODC and has been observed to significantly reduce tumor formation secondary to many different initiators and promoters. Past and ongoing chemoprevention studies of DFMO at the UW and other institutions have revealed significant inhibition in ODC activity and polyamine levels in target tissues at relatively nontoxic doses. Due to concerns about chronic immunosuppressants, like cyclosporine, interfering with the ability to adequately measure promoter-induced ODC activity in skin samples and DFMO effects upon graft survival, an initial phase I pilot study of 0.5 and 1.0 g/day of DFMO in OTR was performed. It revealed that 28 days of 0.5 g/day of DFMO significantly inhibited TPA-induced ODC activity and decreased polyamine (putrescine) levels in skin samples of OTR without toxicity.Prior to pursuing a large phase III study of DFMO in OTR, we propose to perform a phase 2b randomized study of 0.5g/day of DFMO versus placebo for one year in OTR at high risk for skin cancer. The primary endpoint would be a greater than 50% reduction in TPA-induced ODC activity in skin samples for one year. Secondary endpoints will be a 50% decrease in skin putrescine and decreased development of skin lesions (actinic keratoses and carcinomas) for one year. Additional parameters include: toxicity assessment including audio grams for ototoxicity, graft status, compliance, and DFMO and immunosuppressant levels.The importance of assessing the biochemical and potential toxic effects of DFMO in OTR, a population at considerable risk of skin cancer, is magnified further by the increased incidence of multiple malignancies in OTR and the importance of ODC induction in many types of tissue carcinogenesis.